Genetically modified T cells for treating relapsed or refractory acute myeloid leukemia

A Phase I/II Trial of MB-dNPM1-TCR.1 in HLA-A*02:01-positive Patients With Relapsed or Refractory NPM1-mutated AML to Determine Safety and Obtain First Data on Efficacy

This study is testing a new treatment that uses specially modified T cells to see if it can help people with relapsed or hard-to-treat acute myeloid leukemia.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 29 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Miltenyi Biomedicine GmbH (Industry-sponsored)
• Drugs / interventions: chemotherapy, prednisone
• Locations: 1 site (Leiden)
• Trial ID: NCT06424340 on ClinicalTrials.gov

What this trial studies

This Phase I/II trial evaluates the safety, feasibility, and efficacy of MB-dNPM1-TCR.1, a treatment involving autologous T cells that are genetically modified to target specific peptides associated with mutated Nucleophosmin in patients with relapsed or refractory acute myeloid leukemia (AML). The trial consists of a dose escalation phase to determine the maximum tolerated dose, followed by an efficacy evaluation phase using a Simon's minimax design. Patients will undergo leukapheresis, receive lymphodepleting chemotherapy, and then be infused with the modified T cells to target and eliminate malignant myeloid cells.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with relapsed or refractory AML who have the NPM1 mutation and are positive for HLA-A*02:01.

Not a fit: Patients who do not have the NPM1 mutation or are not HLA-A*02:01 positive may not benefit from this treatment.

Why it matters

Potential benefit: If successful, this treatment could provide a novel and effective option for patients with limited treatment alternatives for relapsed or refractory AML.

How similar studies have performed: Other studies using genetically modified T cells for similar conditions have shown promising results, indicating potential for success in this approach.

Eligibility criteria

Inclusion Criteria:

1. Age ≥ 18 years
2. Patients must be able to understand and be willing to give signed informed consent
3. Relapsed or refractory acute myeloid leukemia (last disease staging within 4 weeks prior to screening) without standard treatment options defined as:

   * No morphological CR or extramedullary AML after at least two courses of intensive chemotherapy, decitabine or other standard therapy or
   * MRD positive after at least two courses of intensive chemotherapy or other standard therapy and not eligible for allogeneic stem cell transplantation or
   * Relapsed bone marrow or blood disease or extramedullary AML after CR after first line treatment and not eligible to undergo allogeneic stem cell transplantation or
   * Bone marrow, blood, extramedullary AML relapse or non-response or MRD positivity after allogeneic stem cell transplantation and not eligible to receive Donor Lymphocyte Infusion (DLI) according to local standards, relapse or MRD positive after DLI.
4. Positive for HLA-A\*02:01 according to genotyping results.
5. AML has NPM1 mutation which is recognized by dNPM1-TCR.1 and for which a specific Q-PCR is available for disease monitoring.
6. Number of circulating WBC above 1x109/L with less than 50% leukemic blasts and 0.03 x 109 CD8+ T cells/L.
7. Life expectancy of at least 3 months.
8. ECOG performance status 0-3.
9. Negative pregnancy test in women of childbearing potential.
10. For fertile men and women, agreement to use highly effective contraceptive methods during the trial.

Exclusion Criteria:

1. Pregnant or breast feeding women.
2. Active infection with HIV-1, HIV-2, HBV, HCV, HTLV-I, HTLV-II, SARS-CoV-2 or Treponema Pallidum.
3. Any clinically significant, advanced or unstable disease or inadequate main organ function that may put the patient at increased risk for severe complications of trial participation at the discretion of the investigator.
4. Use of systemic immune suppression including, but not limited to:

   immunosuppressive agents such as cyclosporine or corticosteroids (at an equivalent dose of 0.5 mg prednisone/kg body weight per day, or higher). Inhaled steroid and physiological replacement for adrenal insufficiency are allowed.
5. Unwillingness or inability to comply with procedures required in this clinical trial protocol.
6. Uncontrolled life-threatening infections or uncontrolled disseminated intravascular coagulation; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule.
7. Subjects currently on any other IMP (including within the last 30 days before start of treatment).
8. Current use of high dose immunosuppression for immune disorders interfering with T cell function (on discretion of the investigator).
9. Known hypersensitivity against any drug of the mandatory trial procedures.
10. Serum creatinine ≥ 2.0 × ULN or eGFR \< 30 mL/min calculated according to the modified MDRD formula.
11. BMI ≥40
12. Has received vaccination with live vaccines 6 weeks prior to treatment
13. Major surgery less than 30 days before start of treatment.
14. Committal to an institution on judicial or official order.

Where this trial is running

Leiden

• Leiden University Medical Center — Leiden, Netherlands (Recruiting)

Study contacts

• Principal investigator: C.J.M. Halkes, Dr — Leiden University Medical Center
• Study coordinator: Jörg Liebmann

Conditions Leukemia, Myeloid, Acute